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MLN8237 in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab +/- Vincristine

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ClinicalTrials.gov Identifier: NCT01397825
Recruitment Status : Completed
First Posted : July 20, 2011
Results First Posted : March 27, 2018
Last Update Posted : March 27, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions: Diffuse Large B-Cell Lymphoma
Transformed Follicular Lymphoma
Mantle Cell Lymphoma
Burkitt's Lymphoma
Interventions: Drug: Alisertib (MLN8237)
Drug: Rituximab
Drug: Vincristine

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the Phase 1 portion of the study at 10 investigative sites in the United States from 09 August 2011 to 05 October 2016. The Phase 2 portion of the study was cancelled by the sponsor.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of relapsed or refractory Diffuse Large B-cell lymphoma (DLBCL)/transformed Follicular lymphoma (TFL), Mantle Cell lymphoma, or Burkitt’s Lymphoma were enrolled to receive alisertib open label at doses 30 mg, 40 mg or 50 mg.

Reporting Groups
  Description
Safety Lead-in Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Dose Escalation, Alisertib 30 mg Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Dose Escalation, Alisertib 40 mg Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Phase 2: Alisertib Phase 2: Alisertib (MLN8237) at the Recommended Phase 2 Dose, ECT orally twice/day on Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV on Days 1 & 8 in a 21 Day cycle for up to 8 cycles was planned but not conducted.

Participant Flow:   Overall Study
    Safety Lead-in   Dose Escalation, Alisertib 30 mg   Dose Escalation, Alisertib 40 mg   Dose Escalation, Alisertib 50 mg   Phase 2: Alisertib
STARTED   13   4   25   3   0 
COMPLETED   0   0   0   0   0 
NOT COMPLETED   13   4   25   3   0 
Progressive Disease                10                3                11                1                0 
Symptomatic Deterioration                2                0                4                0                0 
Adverse Event                0                1                5                1                0 
Withdrawal by Subject                1                0                5                1                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population was defined as all participants who receive any amount of alisertib.

Reporting Groups
  Description
Safety Lead-in Alisertib 50 mg, enteric coated tablets (ECT), orally, twice daily (BID), on Days 1 to 7 followed by a 14-day rest period in 21-day cycles plus rituximab 375 mg/m^2, intravenous (IV), infusion on Day 1 of each 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Dose Escalation, Alisertib 30 mg Alisertib 30 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m^2, IV, infusion on Day 1, plus vincristine 1.4 mg/m^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Dose Escalation, Alisertib 40 mg Alisertib 40 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Dose Escalation, Alisertib 50 mg Alisertib 50 mg, ECT, orally, BID, on Days 1 to 7 followed by a 14-day rest period plus rituximab 375 mg/m^2, IV, infusion on Day 1 plus vincristine 1.4 mg/m^2, IV (max 2 mg), on Days 1 and 8 in a 21-day cycle for up to 8 cycles. Following 8 cycles of treatment (or early discontinuation of rituximab and/or vincristine) all participants with documented disease response or stabilization may continue with alisertib single-agent therapy for up to 2 years.
Total Total of all reporting groups

Baseline Measures
   Safety Lead-in   Dose Escalation, Alisertib 30 mg   Dose Escalation, Alisertib 40 mg   Dose Escalation, Alisertib 50 mg   Total 
Overall Participants Analyzed 
[Units: Participants]
 13   4   25   3   45 
Age 
[Units: Years]
Mean (Standard Deviation)
 60.3  (14.06)   51.3  (21.65)   62.8  (10.51)   66.7  (12.86)   61.3  (12.89) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
         
Female      3  23.1%      1  25.0%      10  40.0%      2  66.7%      16  35.6% 
Male      10  76.9%      3  75.0%      15  60.0%      1  33.3%      29  64.4% 
Race/Ethnicity, Customized 
[Units: Participants]
         
Hispanic or Latino   7   1   6   1   15 
Not Hispanic or Latino   6   3   19   2   30 
Race/Ethnicity, Customized 
[Units: Participants]
         
White   12   4   21   3   40 
Black or African American   0   0   2   0   2 
Asian   1   0   0   0   1 
Other   0   0   1   0   1 
Not Reported   0   0   1   0   1 
Region of Enrollment 
[Units: Participants]
         
United States   13   4   25   3   45 
Height 
[Units: Cm]
Mean (Standard Deviation)
 167.9  (10.90)   178.2  (7.15)   168.4  (10.76)   166.5  (5.32)   169.0  (10.44) 
Weight 
[Units: Kg]
Mean (Standard Deviation)
 70.98  (16.18)   89.51  (23.89)   82.21  (16.4)   71.94  (14.55)   78.93  (17.46) 
Body Surface Area [1] 
[Units: M^2]
Mean (Standard Deviation)
 1.815  (0.25)   2.093  (0.31)   1.940  (0.23)   1.823  (0.21)   1.910  (0.25) 


  Outcome Measures

1.  Primary:   Number of Participants With Clinically Significant Vital Signs Findings (Treatment Related and Unrelated) [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

2.  Primary:   Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

3.  Primary:   Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

4.  Primary:   Number of Participants With Clinically Significant Changes in Physical Examination Findings [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

5.  Primary:   Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

6.  Primary:   Number of Participants With Treatment-Emergent Adverse Events [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

7.  Primary:   Overall Response Rate [Phase 2]   [ Time Frame: At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years ]

8.  Secondary:   Overall Response Rate as Assessed by the Investigator [Phase 1]   [ Time Frame: First dose of alisertib through 30 days after the last dose of alisertib (Up to 5.2 Years) ]

9.  Secondary:   Complete Response Rate [Phase 2]   [ Time Frame: Duration of study until disease progression, approximately 2 years ]

10.  Secondary:   Duration of Response (DOR) [Phase 2]   [ Time Frame: Duration of study until disease progression, approximately 2 years ]

11.  Secondary:   Progression Free Survival (PFS) [Phase 2]   [ Time Frame: Duration of study until disease progression, approximately 2 years ]

12.  Secondary:   Number of Participants With Treatment-Emergent Adverse Events [Phase 2]   [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ]

13.  Secondary:   Number of Participants With Clinically Significant Vital Signs Findings [Phase 2]   [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ]

14.  Secondary:   Number of Participants With Clinically Significant Changes in Electrocardiograms (ECGs) [Phase 2]   [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ]

15.  Secondary:   Number of Participants With Clinically Significant Changes in Multigated Acquisition (MUGA)/ Echocardiogram (ECHO) [Phase 2]   [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ]

16.  Secondary:   Number of Participants With Clinically Significant Laboratory Tests Reported as Adverse Events [Phase 2]   [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ]

17.  Secondary:   Cmax: Maximum Plasma Concentration for Alisertib   [ Time Frame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose ]

18.  Secondary:   Tmax: Time to First Occurrence of Cmax fo Alisertib   [ Time Frame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose ]

19.  Secondary:   AUCt: Area Under the Concentration Time Curve Over the Dosing Interval From Time 0 to Time t for Alisertib   [ Time Frame: Cycle 1 Days 1 and 7 prior to morning alisertib dose and multiple time-points (up to 12 hours) post-dose ]

20.  Secondary:   Cmax: Maximum Plasma Concentration for Vincristine   [ Time Frame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose ]

21.  Secondary:   AUCt: Area Under the Concentration-time Time Curve Over the Dosing Interval From Time 0 to Time t for Vincristine   [ Time Frame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose ]

22.  Secondary:   AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for Vincristine   [ Time Frame: Cycles 1 and 2 on Day 1 prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose ]

23.  Secondary:   T1/2: Terminal Disposition Phase Half-life for Vincristine   [ Time Frame: Cycles 1 and 2 on Day prior to injection of vincristine and multiple time-points (up to 72 hours) post-dose ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The Phase 2 portion of the study was cancelled by the sponsor; this was an administrative decision not based on any clinical or safety outcomes.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director
Organization: Takeda
phone: +1-877-825-3327
e-mail: trialdisclosures@takeda.com



Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier: NCT01397825     History of Changes
Other Study ID Numbers: C14011
2011-000609-32 ( EudraCT Number )
U1111-1181-0333 ( Registry Identifier: WHO )
12/NE/0268 ( Registry Identifier: NRES )
First Submitted: July 17, 2011
First Posted: July 20, 2011
Results First Submitted: January 4, 2018
Results First Posted: March 27, 2018
Last Update Posted: March 27, 2018